Patent EP-0170926-B1 (EP)
IPC: A61K31/475
Filed: 1985-07-11
Granted: 1990-02-28
Abstract: 1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, NL, SE Eburnanecarboxylic acid derivatives which have at position 9 or 11 an optionally substituted amino group and are of the general formula  see diagramm : EP0170926,P30,F1  wherein R stands for an amino group or an acylamino residue of the general formula  see diagramm : EP0170926,P30,F2  in which R**1 is hydrogen or an aliphatic hydrocarbon residue having 1 to 10 carbon atom(s), a cycloaliphatic hydrocarbon residue having 3 to 8 carbon atoms, an aromatic hydrocarbon residue having 6 to 14 carbon atoms or a 5- to 7-membered heteroaryl residue having one or more identical or different heteroatoms consisting of nitrogen, oxygen and/or sulphur, and optionally having in addition to said members 4 members which have been fused on to form a benzene ring, wherein the above-mentioned residues are optionally substituted with one or more identical or different substituents consisting of halogen atoms, primary, secondary and tertiary amino groups, hydroxy groups, aryl residues having 6 to 14 carbon atoms, trifluoromethyl residues, carboxyl groups, alkoxy-carbonyl residues having 1 to 8 carbon atoms in the alkyl moiety, thio, sulphinyl, sulphonyl, nitro, keto, aldehyde and cyano groups and 1 or more 5- to 7-membered heteroaryl residues containing nitrogen, oxygen and/or sulphur as heteroatoms and having optionally in addition to said members 4 members which have been fused on to form a benzene ring, particularly pyrrolyl, furyl, thienyl, pyridyl, pyranyl, pyrazolyl, imidazolyl, pyrimidinyl, indolyl and quinolyl residues, which may optionally be substituted with 1 or more of the listed substituents, or a sulphonamido residue of the general formula  see diagramm : EP0170926,P30,F3  in which R**2 is an aliphatic hydrocarbon residue having 1 to 10 carbon atom(s) or an aromatic hydrocarbon residue having 6 to 14 carbon atoms, wherein said residues may be substituted with one or more of the substituents listed in connection with R**1 , R**3 is hydrogen or an aliphatic hydrocarbon residue having 1 to 10 carbon atom(s), a cycloaliphatic hydrocarbon residue having 3 to 8 carbon atoms or an aromatic hydrocarbon residue having 6 to 14 carbon atoms, which residues may be substituted with 1 or more identical or different ones of the substituents listed in connection with R**1 , A stands for a hydroxy group, B means hydrogen or A and B together represent a chemical bond and R is in position 9 or 11, provided that a) if R stands for an amino group, then R**3 is different from an unsubstituted methyl residue and b) if R stands for an acylamido residue which is in position 9 or 11 and has the general formula II, in which R**1 is a methyl residue, A represents a hydroxy group and B represents hydrogen, then R**3 is different from an unsubstituted methyl residue, and their optically active isomers and salts. 1. Claims for the Contracting State : AT A process of producing eburnanecarboxylic acid derivatives which have at position 9 or 11 an optionally substituted amino group and are of the general formula see diagramm : EP0170926,P33,F3  wherein R stands for an amino group or an acylamino residue of the general formula  see diagramm : EP0170926,P34,F1  in which R**1 is hydrogen or an aliphatic hydrocarbon residue having 1 to 10 carbon atom(s), a cycloaliphatic hydrocarbon residue having 3 to 8 carbon atoms, an aromatic hydrocarbon residue having 6 to 14 carbon atoms or a 5- to 7-membered heteroaryl residue having one or more identical or different heteroatoms consisting of nitrogen, oxygen and/or sulphur, and optionally having in addition to said members 4 members which have been fused on to form a benzene ring, wherein the above-mentioned residues are optionally substituted with one or more identical or different substituents consisting of halogen atoms, primary, secondary and tertiary amino groups, hydroxy groups, aryl residues having 6 to 14 carbon atoms, trifluoromethyl residues, carboxyl groups, alkoxy-carbonyl residues having 1 to 8 carbon atoms in the alkyl moiety, thio, sulphinyl, sulphonyl, nitro, keto, aldehyde and cyano groups and 1 or more 5- to 7-membered heteroaryl residues containing nitrogen, oxygen and/or sulphur as heteroatoms and having optionally in addition to said members 4 members which have been fused on to form a benzene ring, particularly pyrrolyl, furyl, thienyl, pyridyl, pyranyl, pyrazolyl, imidazolyl, pyrimidinyl, indolyl and quinolyl residues, which may optionally be substituted with 1 or more of the listed substituents, or a sulphonamido residue of the general formula  see diagramm : EP0170926,P34,F2  in which R**2 is an aliphatic hydrocarbon residue having 1 to 10 carbon atom(s) or an aromatic hydrocarbon residue having 6 to 14 carbon atoms, wherein said residues may be substituted with one or more of the substituents listed in connection with R**1 , R**3 is hydrogen or an aliphatic hydrocarbon residue having 1 to 10 carbon atom(s), a cycloaliphatic hydrocarbon residue having 3 to 8 carbon atoms or an aromatic hydrocarbon residue having 6 to 14 carbon atoms, which residues may be substituted with 1 or more identical or different ones of the substituents listed in connection with R**1 , A stands for a hydroxy group, R means hydrogen or A and B together represent a chemical bond and R is in position 9 or 11, provided that a) if R stands for an amino group, then R**3 is different from an unsubstituted methyl residue and b) if R stands for an acylamido residue which is in position 9 or 11 and has the general formula II, in which R**1 is a methyl residue, A represents a hydroxy group and B represents hydrogen, then R**3 is different from an unsubstituted methyl residue, and their optically active isomers and salts, characterised in that a) racemic or optically active eburnanecarboxylic acid derivatives of the general formula  see diagramm : EP0170926,P34,F3  in which R**4 stands for a methyl residue or, if A and B together represent a chemical bond, may also represent hydrogen and the amino group is in position 9 or 11, or their salts, optionally after a hydrolysis, are acylated except acetylation in the case that R**4 stands for a methyl residue, A represents a hydroxy group and B represents hydrogen, and alpha) the resulting eburnanecarboxylic acid derivatives of the general formula I in which R stands for an acylamido residue of the general formula II or a sulphonylamido residue of the general formula III in which R**1 and R**2 have the meaning stated in claims 1 to 10, A and B have the meanings stated in claim 1 and R**3 has the meaning of R**4 , or the salts thereof are optionally esterified or transesterified and/or beta) the resulting eburnanecarboxylic acid derivatives of the general formula I in which R stands for an acylamido residue of the general formula II or far a sulphonamido residue of the general formula III in which R**1 and R**2 have the meanings stated in claims 1 to 10, A stands for a hydroxy group, B represents hydrogen and R**3 is different from hydrogen, or the salts thereof are optionally hydrolyzed, and/or gamma) the resulting eburnanecarboxylic acid derivatives of the general formula I in which R and R**3 have the meanings stated in claims 1 to 10, A stands for a hydroxy group and B represents hydrogen, or their salts are optionally dehydrated or b) racemic or optically active eburnanecarboxylic acid derivatives having the general formula  see diagramm : EP0170926,P35,F1  in which R**4 stands for a methyl residue or, if A and B together represent a chemical bond, may also represent hydrogen and the amino group is in position 9 or 11, or their salts are esterified or transesterified and alpha) the resulting eburnanecarboxylic acid derivatives of the general formula I, in which R stands for an amino group, A stands for a hydroxy group, a represents hydrogen and R**3 is different from hydrogen, or the salts thereof are optionally hydrolyzed, and/or beta) the resulting eburnanecarboxylic acid derivatives of the general formula I in which R and R**3 have the meanings stated in claims 1 to 10, A stands for a hydroxy group and a represents hydrogen, or their salts are optionally dehydrated and/or gamma) the resulting eburnanecarboxylic acid derivatives of the general formula I, in which R stands for an amino group and R**3 , A and B have the meanings stated in claims 1 to 7, 9 or 10 or stands for an unsubstituted methyl residue, or their salts are optionally acylated or c) racemic or optically active 9- or 11- (nitro)-eburnanecarboxylic acid derivatives of the general formula see diagramm : EP0170926,P35,F2  in which R**3 , A and B have the meanings stated in claims 1 to 7, 9 or 10 and the nitro group is in position 9 or 11 are reduced and the reactions according to a) alpha) and/or a) beta) and/or b) alpha) and/or a) gamma) and/or b) beta) and/or b) gamma) are optionally carried out and the resulting eburnanecarboxylic acid derivatives of the general formula I are optionally converted to acid addition salts or quaternary salts and/or the resulting salts of the eburnanecarboxylic acid derivatives of the general formula I are optionally converted to the free eburnanecarboxylic acid derivatives of the general formula I or to other acid addition salts and/or quaternary salts and/or the resulting racemic eburnanecarboxylic acid derivatives of the general formula I and/or their acid addition salts and/or quaternary salts optionally split and/or the corresponding optically active compounds are optionally racemized to stereoisomers.